1. Field of the Invention
The present invention relates generally to the fields of biomedical physics and drug delivery. More specifically, the present invention provides feedback devices and methods for controlling the alteration of biological membranes and the permeation of substances across biological membranes.
2. Description of the Related Art
Various methods have been used for facilitating the delivery of compounds across the skin and other membranes. Iontophoresis uses an electric current to increase the permeation rate of charged molecules. However, iontophoresis is dependent on charge density of the molecule and has further been known to cause burning in patients. Use of ultrasound has also been tested whereby application of ultrasonic energy to the skin results in a transient alteration of the skin, which leads to an increased permeability to substances. Electromagnetic energy produced by lasers may be used to ablate the stratum corneum in order to make the skin more permeable to pharmaceutical substances (see U.S. Pat. No. 4,775,361). Impulse transients generated by lasers or by mechanical means may be used to make alterations in epithelial layers that result in improved permeation of compounds (see U.S. Pat. No. 5,614,502).
In general, permeation of drugs through the skin occurs at a very slow rate, if at all. The primary rate limiting step in this process is the passage of these compounds through the outermost layer of skin, called the stratum corneum. The stratum corneum is a very thin layer of dead cells that acts as an impermeable layer to matter on either side of this layer. The stratum corneum primarily provides the skin's barrier function. It has long been recognized that loss or alteration of the stratum corneum results in increased permeability to many substances; materials can more easily diffuse into or out of the skin. It has also been demonstrated that electromagnetic energy induced alterations of the stratum corneum result in increased permeability to substances U.S. Pat. Nos. 6,315,722, 6,251,100, 6,056,738 and 5,643,252. Alternatively, compounds referred to as permeation enhancers, e.g., alcohol or drug carriers such as liposomes, can be used, with some success, to penetrate the stratum corneum. The barrier function of the skin presents a very significant problem to pharmaceutical manufacturers interested in topical administration of drugs or in cutaneous collection of bodily fluids.
Electrosurgery is a method whereby tissue coagulation and/or dissection can be effected. In electrosurgery, radiofrequency (RF) current is applied to tissue by an active electrode. In a bipolar system, the current is passed through tissue between two electrodes on the same surgical instrument, such as a forceps. In a monopolar system, a return-path (ground) electrode is affixed in intimate electrical contact with some part of the patient. Because of the importance of the ground electrode providing the lowest impedance conductive path for the electrical current, protection circuits monitoring the contact of the ground with the patient are often employed wherein an increase in ground electrode-skin impedance results in the instrument shutting down. A desired alteration in the tissue, usually coagulation or cutting, can be made by manipulating the treatment electrode shape, the electrode position (contact or non-contact) with respect to the tissue surface, frequency and modulation of the radiofrequency current, power of the radiofrequency current and the length of time for which it is applied to the tissue surface, and peak-to-peak voltage of the radiofrequency current with respect to the tissue type.
For example, decreasing electrode size translates into increased current density in the tissue proximal to the electrode and so a more invasive tissue effect, such as dissection as compared to coagulation, is realized. Similarly, if the electrode is held close to the tissue but not in contact, then the area of radiofrequency-tissue interaction is smaller as compared to the area when the electrode is in contact with the tissue, therefore, the effect on the tissue is more invasive. By changing the waveform of the applied radiofrequency current from a continuous sinusoid to packets of higher peak voltage sinusoids separated by dead time (for example, with a duty cycle of 6%), then the tissue effect can be changed from dissection to coagulation. Increasing the voltage of the waveform increases the invasiveness of the tissue effect, and the longer the tissue is exposed to the radiofrequency, the greater the tissue effect. Finally, different tissues respond to radiofrequency differently because of their different electrical conductive properties, concentration of current carrying ions, and different thermal properties. In a typical electrosurgical system, radiofrequency frequencies of 300 kHz to 4 MHz are used since nerve and muscle stimulation cease at frequencies beyond 100 kHz.
Devices incorporating radiofrequency electrodes for use in electrosurgical and electrocautery techniques are described in Rand1 et al. and U.S. Pat. Nos. 5,281,216; 4,943,290; 4,936,301; 4,593,691; 4,228,800; and 4,202,337.
U.S. Pat. Nos. 4,943,290 and 4,036,301 describe methods for injecting non-conducting liquid over the tip of a monopolar electrosurgical electrode to electrically isolate the electrode, while energized, from a surrounding electrically conducting irrigant.
U.S. Pat. Nos. 5,195,959 and 4,674,499 describe monopolar and bipolar electrosurgical devices, respectively, that include a conduit for irrigating the surgical site.
U.S. Pat. Nos. 5,217,455, 5,423,803, 5,102,410, 5,282,797, 5,290,273, 5,304,170, 5,312,395, 5,336,217 describe laser treatment methods for removing abnormal skin cells, such as pigmentations, lesions, soft tissue and the like.
U.S. Pat. Nos. 5,445,634 and 5,370,642 describe methods for using laser energy to divide, incise or resect tissue during cosmetic surgery. U.S. Pat. No. 5,261,410 is directed to a method and apparatus for detecting and removing malignant tumor tissue.
U.S. Pat. Nos. 5,380,316, 4,658,817, 5,389,096, International Publication WO 94/14383 and European Patent Application No. 0515867 describe methods and apparatus for percutaneous myocardial revascularization. These methods and apparatus involve directing laser energy against the heart tissue to form transverse channels through the myocardium to increase blood flow from the ventricular cavity to the myocardium.
Devices and methods in U.S. Pat. Nos. 5,683,366, 5,697,536, 6,228,078, and 5,888,198 describe bipolar and monopolar radiofrequency electrosurgical devices that use a method of tissue disintegration as a means to ablate tissue prior to myocardial revascularization, tissue resurfacing or other surgical procedures.
Devices and methods for drug delivery using laser ablation systems have been described. U.S. Pat. No. 6,251,100 provides an improved method of administering a pharmaceutical composition, such as an anesthetic through the skin of a patient without the use of a sharp or needle. This method includes the step of irradiating the stratum corneum of a region of the skin of the patient using a laser. By a selection of parameters, the laser irradiates the surface of the skin precisely to a selectable depth, without causing clinically relevant damage to healthy proximal tissue. A pharmaceutical composition is then applied to the region of irradiation. International Publication WO 00/57951 describes the use of non-ionizing energy, including lasers, to improve methods of administering pharmaceuticals in tissues, including the skin. In the case of RF energy, certain applications describe feedback mechanisms that are used to prevent damage to viable tissue in the area surrounding the treatment site including U.S. Patent Publication No. 2002/0010414 A1 and WO 01/21068.
It is notable that consistent means of treatment are desirable. The Code of Federal Regulations (21 CFR 860.7(e)(1)) establishes that there is “reasonable assurance that a device is effective when it can be determined, based upon valid scientific evidence, that in a significant portion of the target population, the use of the device . . . will provide clinically significant results.” Devices that cannot be shown to provide consistent results between patients, or even within a patient upon multiple use, will have minimal utility and may not be approvable for broad use.
Beyond devices, it is generally desirable to develop medical products with critical controls that can deliver a precise result. Of critical concern is the delivery of many types of drugs. Certain drugs can be described as having a “broad” or “narrow” therapeutic index (TI). That is, some drugs may be useful over a broad range of concentrations (broad TI), and thus are safe for the general population, while other drugs may only be effective over a narrow concentration range (narrow TI) and may even be dangerous when administered in greater than recommended concentrations. This is particularly true where a drug has a narrow therapeutic index; the delivery of the drug must be controlled carefully so as to avoid potentially harmful effects.
The FDA in its PMA Memorandum #P91-1: Clinical Utility and Premarket Approval has established that devices that cannot be controlled may have limited utility. Particularly a drug delivery device may have limited utility if no assurance can be made that a consistent dosage is delivered throughout the patient population. The drug-device combination must be capable of consistently delivering a dosage. As part of INDs and NDAs for administered drug products, bioavailability studies focus on determining the process by which a drug is released from the oral dosage form and moves to the site of action.
Bioavailability data provide an estimate of the fraction of the drug absorbed, as well as the drug's subsequent distribution and elimination. Bioavailability is defined in 21 CFR 320.1 as “the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.” This definition focuses on the processes by which the active ingredients or moieties are released from a dosage form and move to the site of action. A delivery device which does not consistently release the same levels of a drug product due to the design of a product will have limited clinical utility as there can be no assurance that a certain dosage has been delivered at any point in time.
Furthermore, studies to establish bioequivalence between two products are important to demonstrated safety and therapeutic efficacy in a product and will be a benchmark for approval of drugs by regulatory bodies. Bioequivalence is defined at 21 CFR 320.1 as “the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.” As noted in the statutory definitions, both bioequivalence and product quality bioavailability focus on the release of a drug substance from a drug product and subsequent absorption into the systemic circulation. Where the test product generates variable effect at the site of action, as compared to those of the reference product, the product cannot be claimed as consistent, will not have great clinical utility and could be dangerous to use.
Control of delivery for transdermal applications is achieved by delivering a fraction of what is “absorbable,” and either regulating the size of the dosage or the amount that is released from the vehicle. The condition of the skin and its hydration are significant factors in the percutaneous absorption of drugs. Some solubility of the substance in both lipid and water is thought to be essential. The aqueous solubility of a drug determines the concentration presented to the absorption site and the partition coefficient strongly influences the rate of absorption across the absorption site (Pharmaceutical Dosage Forms and Drug Delivery Systems, Ansel, H. C., Popovich, N. G. Allen, L. V. Eds., Williams & Wilkins, Baltimore, 1995.) Vehicles that increase the hydration of the skin generally favor percutaneous absorption of drugs.
The inventors have recognized a need in the art for a device and improved methods of controllably facilitating permeation of substances across tissue membranes. Whereas mechanisms are published for protecting viable tissue surrounding the treatment site, the prior art is deficient in methods to achieve control over the alteration event in order to achieve variable rates of permeability. Specifically, the use of energy to alter the permeability of a biological membrane to a pharmaceutical or other biological molecule has been reported, however, the literature is deficient in reports of methods for controlling the treatment process in order to achieve a desired state of permeability.